From Regular Catharsis with Castor Oil to Recognizing the Importance of the Intestinal Microbiota.

The need to shed light on the unknown aspects of pathophysiology of common disorders, such as gastrointestinal ones, has led researchers through last decades to study and define the role of microorganisms within the human intestine and their interactions with the host. The progress of technology has permitted the overcoming of culture-based methods to study microbes and paved the way to molecular techniques, which allow the analysis of microbial genome, microbial functions, and metabolism. These progresses opened a window on the world of microbiology and permitted to deepen into the key role played by gut microbiota and dysbiosis in health status and diseases, both gastrointestinal and extraintestinal. So, scientists focused their attention in developing new strategies to restore eubiosis and to manipulate gut microbes by modifying dietary habits, administrating antibiotics, probiotics, and prebiotics and using fecal microbiota transplantation as treatment of gastrointestinal, infectious, cardiovascular, metabolic, immune-mediated, neuro-psychiatric, and oncological disorders. The next challenges will be to elaborate standard protocols with definite outcomes predictors in disease-specific settings.

European consensus conference on faecal microbiota transplantation in clinical practice.

Faecal microbiota transplantation (FMT) is an important therapeutic option for Clostridium difficile infection. Promising findings suggest that FMT may play a role also in the management of other disorders associated with the alteration of gut microbiota. Although the health community is assessing FMT with renewed interest and patients are becoming more aware, there are technical and logistical issues in establishing such a non-standardised treatment into the clinical practice with safety and proper governance. In view of this, an evidence-based recommendation is needed to drive the practical implementation of FMT. In this European Consensus Conference, 28 experts from 10 countries collaborated, in separate working groups and through an evidence-based process, to provide statements on the following key issues: FMT indications; donor selection; preparation of faecal material; clinical management and faecal delivery and basic requirements for implementing an FMT centre. Statements developed by each working group were evaluated and voted by all members, first through an electronic Delphi process, and then in a plenary consensus conference. The recommendations were released according to best available evidence, in order to act as guidance for physicians who plan to implement FMT, aiming at supporting the broad availability of the procedure, discussing other issues relevant to FMT and promoting future clinical research in the area of gut microbiota manipulation. This consensus report strongly recommends the implementation of FMT centres for the treatment of C. difficile infection as well as traces the guidelines of technicality, regulatory, administrative and laboratory requirements.

Probiotics History.

Gut microbiota promotes healthy effects on the host and prevents diseases. Probiotic (probios, for life) are defined as "live microorganisms which when administered in adequate amounts confer a health benefit on the host." At the beginning of 1900s Louis Pasteur identified the microorganisms responsible for the process of fermentation, whereas E. Metchnikoff associated the enhanced longevity of Bulgarian rural people to the regular consumption of fermented dairy products such as yogurt. He suggested that lactobacilli might counteract the putrefactive effects of gastrointestinal metabolism that contributed to illness and aging. Hippocrates declared, 2000 years earlier, that "death sits in the bowels." Metchnikoff considered the lactobacilli as probiotics ("probios," conducive to life of the host as opposed to antibiotics); probiotics could have a positive influence on health and prevent aging. During the neolitic period of the age of the stone, the domestication of animals occurred and man began to get fermented food. Probably serendipitous contaminations in favorable environments played a major role. Fecal microbiota transplantation dates to a fourth-century Chinese handbook for food poisoning or severe diarrhea. To date fecal transplant cures Clostridium difficile infections with more efficacy than vancomycin, and prevents recurrence.

Helicobacter pylori and extragastric diseases.

While Helicobacter pylori infection was initially revealed to be associated only with some gastroduodenal diseases, further studies have shown its possible role in several extragastric diseases. For idiopathic thrombocytopenic purpura, sideropenic anemia, and vitamin B12 deficiency, the diagnosis of H. pylori infection is recommended, and there are many other conditions such as cardiovascular, neurological, dermatological, and respiratory diseases in which H. pylori may possibly play a role. Interestingly, a potential role has also been described for GI neoplastic diseases, including colorectal and pancreatic cancer. Different mechanisms of action have been proposed, ranging from the induction of a low grade inflammatory state to the occurrence of molecular mimicry mechanisms. This review summarizes the results of the most relevant studies published on this topic over the last year.

Palaeodiet reconstruction in a woman with probable celiac disease: a stable isotope analysis of bone remains from the archaeological site of Cosa (Italy).

Stable isotope analysis in the reconstruction of human palaeodiets can yield clues to early human subsistence strategies, origins and history of farming and pastoralist societies, and intra- and intergroup social differentiation. In the last 10 years, the method has been extended to the pathological investigation. Stable isotope analysis to better understand a diet-related disease: celiac disease in ancient human bones was carried out. To do this, we analyzed the nitrogen and carbon isotopic composition of human (n = 37) and faunal (n = 8) bone remains from the archaeological site of Cosa at Ansedonia, on the Tyrrhenian coast near Orbetello (Tuscany), including the skeletal remains of a young woman (late 1st century-early 2nd century Common Era [CE]) with morphological and genetic features suggestive of celiac disease. We compared the young woman's isotopic data with those of other individuals recovered at the same site but from two later time periods (6th century CE; 11-12th century CE) and with literature data from other Italian archaeological sites dating to the same period. Her collagen δ(13) C and δ(15) N values differed from those of the samples at the same site, and from most but not all of the contemporary sites. Although the woman's diet appears distinct, chronic malnutrition resulting from severe malabsorption of essential nutrients due to celiac disease may have affected the isotopic composition of her bone collagen.

Liver transplantation in alcoholic patients: impact of an alcohol addiction unit within a liver transplant center.

BACKGROUND: Many concerns about liver transplantation in alcoholic patients are related to the risk of alcohol recidivism. Starting from 2002, an Alcohol Addiction Unit (AAU) was formed within the liver transplant center for the management of alcoholic patients affected by end-stage liver disease and included in the waiting list for transplantation. We evaluated retrospectively the impact of the AAU on alcohol recidivism after transplantation. The relationship between alcohol recidivism and the duration of alcohol abstinence before transplant was evaluated as well. METHODS: Between 1995 and 2010, 92 cirrhotic alcoholic patients underwent liver transplantation. Clinical evaluation and management of alcohol use in these patients was provided by psychiatrists with expertise in addiction medicine not affiliated to the liver transplant center before 2002 (n = 37; group A), or by the clinical staff of the AAU within the liver transplant center starting from 2002 (n = 55; group B). RESULTS: Group B, as compared with group A, showed a significantly lower prevalence of alcohol recidivism (16.4 vs. 35.1%; p = 0.038) and a significantly lower mortality (14.5 vs. 37.8%; p = 0.01). Furthermore, an analysis of group B patients with either ≥6 or <6 months of alcohol abstinence before transplantation showed no difference in the rate of alcohol recidivism (21.1 vs. 15.4%; p = ns). CONCLUSIONS: The presence of an AAU within a liver transplant center reduces the risk of alcohol recidivism after transplantation. A pretransplant abstinence period <6 months might be considered, at least in selected patients managed by an AAU.

Sorghum (Sorghum vulgare): an ancient grain, a novel choice for a healthy gluten-free diet.

Celiac disease (CD) is an autoimmune disease related to gluten consumption. To date, the only effective therapy that can reverse symptoms and prevent complications is the gluten-free diet (GFD), which is challenging to maintain and has potential health risks. Identifying foods that can help diversify the GFD and that best match the nutritional needs of people with CD may improve the health and quality of life of celiac patients. This review, conducted through a non-systematic search of the available literature, aims to gather the most recent research on nutritional issues in CD and GFD. Moreover, it highlights how sorghum characteristics could provide health benefits to CD patients that counteract the nutritional problems due to CD and the nutritional consequences of GFD acceptance. Sorghum contains a wide variety of bioactive compounds, such as flavones and tannins, that have shown anti-inflammatory activity in preclinical studies. They can also regulate blood sugar levels and lower cholesterol to reduce the effects of common chronic diseases such as metabolic and cardiovascular diseases. Because it is gluten-free, its use in making foods for celiac patients is increasing, especially in the United States. In conclusion, sorghum is a fascinating grain with nutritional properties and health benefits for supplementing GFD. However, only one study confirms the short-term safety of sorghum inclusion in the GFD, and further long-term studies with a large sample are needed.

Antibodies anti-CagA cross-react with trophoblast cells: a risk factor for pre-eclampsia?

BACKGROUND: Previous studies reported an epidemiological association between CagA-positive H. pylori strains and pre-eclampsia. As antibodies anti-CagA cross-react with endothelial cells and trophoblast cells show an endothelial phenotypic profile, we hypothesized that anti-CagA antibodies may recognize antigens of cytotrophoblast cells, thus impairing their function. MATERIALS AND METHODS: Placenta samples were obtained from healthy women. Cytotrophoblast cells were cultured in a medium containing increasing concentration of polyclonal anti-CagA antibodies. Binding of anti-CagA antibodies to cytotrophoblast cells was evaluated by cell ELISA and immunofluorescence assay. Invasive potential of those cells was assessed by an invasion culture system and by measuring of MMP-2. Protein sequencing was performed on antigens precipitated by anti-CagA antibodies. Measurement of phosphorylated ERK expression and NF-kB DNA-binding activity in trophoblast cells incubated with anti-CagA or irrelevant antibodies was also performed. RESULTS: Anti-CagA antibodies recognized ß-actin of cytotrophoblast cells, showing a dose-dependent binding. Incubation of cytotrophoblast cells with increasing doses of anti-CagA antibodies significantly reduced their invasiveness and determined a significant decrease in phosphorylated ERK expression and a reduced NF-kB translocation activity. CONCLUSIONS: This study shows that anti-CagA antibodies recognize ß-actin of cytotrophoblast cells, reducing their invasiveness ability, possibly giving a biological explanation for the epidemiological association.

Therapeutic implications of mesenchymal stem cells in liver injury.

Mesenchymal stem cells (MSCs), represent an attractive tool for the establishment of a successful stem-cell-based therapy of liver diseases. A number of different mechanisms contribute to the therapeutic effects exerted by MSCs, since these cells can differentiate into functional hepatic cells and can also produce a series of growth factors and cytokines able to suppress inflammatory responses, reduce hepatocyte apoptosis, regress liver fibrosis, and enhance hepatocyte functionality. To date, the infusion of MSCs or MSC-conditioned medium has shown encouraging results in the treatment of fulminant hepatic failure and in end-stage liver disease in experimental settings. However, some issues under debate hamper the use of MSCs in clinical trials. This paper summarizes the biological relevance of MSCs and the potential benefits and risks that can result from translating the MSC research to the treatment of liver diseases.

Dose-response effect of baclofen in reducing daily alcohol intake in alcohol dependence: secondary analysis of a randomized, double-blind, placebo-controlled trial.

AIMS: To explore the effect of baclofen in a dose of 20 mg three times per day, compared with the already studied dose of 10 mg three times per day, in the treatment of alcohol dependence. METHODS: We present a secondary analysis of a 12-week double-blind, placebo-controlled, randomized clinical trial with two doses of baclofen, specifically 10 mg t.i.d. and 20 mg t.i.d. Out of 94 subjects consecutively screened, 42 were randomized into the study. Fourteen of the 42 patients were randomly allocated to placebo, 14 to the group treated with baclofen 10 mg t.i.d. (B10 mg) and 14 to the group treated with baclofen 20 mg t.i.d. (B20 mg). RESULTS: Compared with patients allocated to placebo, patients allocated to the B10 mg group had a 53% reduction in the number of drinks per day (P < 0.0001) and patients allocated to the B20 mg group had a 68% reduction in the number of drinks per day (P < 0.0001), with respect to the number of drinks per day during the 28 days before randomization. The effect of baclofen 20 mg t.i.d. was greater than that of baclofen 10 mg t.i.d. (P = 0.0214, Wald test) showing a dose-effect relationship. Both doses of baclofen were well tolerated. CONCLUSION: This is provisional evidence of a dose-response effect for baclofen in the treatment of alcohol dependence.

Nonlinear machine learning pattern recognition and bacteria-metabolite multilayer network analysis of perturbed gastric microbiome.

The stomach is inhabited by diverse microbial communities, co-existing in a dynamic balance. Long-term use of drugs such as proton pump inhibitors (PPIs), or bacterial infection such as Helicobacter pylori, cause significant microbial alterations. Yet, studies revealing how the commensal bacteria re-organize, due to these perturbations of the gastric environment, are in early phase and rely principally on linear techniques for multivariate analysis. Here we disclose the importance of complementing linear dimensionality reduction techniques with nonlinear ones to unveil hidden patterns that remain unseen by linear embedding. Then, we prove the advantages to complete multivariate pattern analysis with differential network analysis, to reveal mechanisms of bacterial network re-organizations which emerge from perturbations induced by a medical treatment (PPIs) or an infectious state (H. pylori). Finally, we show how to build bacteria-metabolite multilayer networks that can deepen our understanding of the metabolite pathways significantly associated to the perturbed microbial communities.

Biofilm demolition and antibiotic treatment to eradicate resistant Helicobacter pylori: a clinical trial.

BACKGROUND & AIMS: Helicobacter pylori attaches to gastric mucosa and grows as a biofilm. This constitutes protection from antimicrobial agents. We assessed the role of a pretreatment with n-acetylcysteine in destroying biofilm and overcoming H pylori antibiotic resistance. METHODS: In an open-label, randomized controlled trial, 40 subjects with a history of at least 4 H pylori eradication failures were evaluated for biofilm presence, antibiotic susceptibility, and H pylori genotypes. Subjects were assigned randomly to receive (group A) or not (group B) n-acetylcysteine before a culture-guided antibiotic regimen. The primary end point was the H pylori eradication rate as assessed by (13)C-labeled urea breath testing. RESULTS: H pylori was eradicated in 13 of 20 (both per-protocol and intention-to-treat analyses, 65%; 95% confidence interval, 44%-86%) group A participants and 4 of 20 (both per-protocol and intention-to-treat analyses, 20%; 95% confidence interval, 3%-37%) group B participants (P < .01). Biofilms persisted only in unsuccessfully treated participants. H pylori genotypes did not influence treatment outcome. CONCLUSIONS: N-acetylcysteine pretreatment before a culture-guided antibiotic regimen is effective in overcoming H pylori antibiotic resistance.

Anti-tissue transglutaminase antibodies from celiac patients are responsible for trophoblast damage via apoptosis in vitro.

OBJECTIVES: The association between maternal celiac disease (CD) and both reduced fertility and increased risk of adverse pregnancy-related events has been long documented. However, no evidences are available regarding the pathogenic mechanisms of this link. The aim of this study was to determine whether anti-tissue transglutaminase (anti-tTG) antibodies are involved in the damage of trophoblastic cells in vitro. METHODS: Human primary trophoblastic cells, isolated from term placenta, were exposed to anti-tTG immunoglobulin G (IgG) antibodies, both commercially available and separated from sera of three untreated celiac women. The ability of anti-tTG antibodies to bind to trophoblastic cells, invasiveness of placental cells through a layer of extracellular matrix, and the activity of cellular matrix metalloprotease (MMP) and cellular apoptosis were evaluated, as indicators of trophoblast damage, by TdT-mediated dUTP digoxigenin nick end labeling (TUNEL) and annexin V expression. RESULTS: Anti-tTG IgG showed a specific dose- and time-dependent binding to human trophoblast. In addition, trophoblastic cells, after being exposed to anti-tTG IgG antibodies, both commercially available and separated from sera of celiac women, showed an impaired invasiveness, a decreased activity of cellular MMP, and a greater percentage of TUNEL positivity and annexin V positivity. CONCLUSIONS: We showed that the binding of anti-tTG antibodies to trophoblast might represent a key mechanism by which the embryo implantation and pregnancy outcome are impaired in untreated celiac pregnant women. Because healthy trophoblast development is essential for placental and fetal development, these data provide a novel mechanism for CD-induced infertility, early pregnancy loss, and intrauterine growth retardation.

Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease.

UNLABELLED: The role played by the gut in nonalcoholic fatty liver disease (NAFLD) is still a matter of debate, although animal and human studies suggest that gut-derived endotoxin may be important. We investigated intestinal permeability in patients with NAFLD and evaluated the correlations between this phenomenon and the stage of the disease, the integrity of tight junctions within the small intestine, and prevalence of small intestinal bacterial overgrowth (SIBO). We examined 35 consecutive patients with biopsy-proven NAFLD, 27 with untreated celiac disease (as a model of intestinal hyperpermeability) and 24 healthy volunteers. We assessed the presence of SIBO by glucose breath testing (GBT), intestinal permeability by means of urinary excretion of (51)Cr-ethylene diamine tetraacetate ((51)Cr-EDTA) test, and the integrity of tight junctions within the gut by immunohistochemical analysis of zona occludens-1 (ZO-1) expression in duodenal biopsy specimens. Patients with NAFLD had significantly increased gut permeability (compared with healthy subjects; P < 0.001) and a higher prevalence of SIBO, although both were lower than in the untreated celiac patients. In patients with NAFLD, both gut permeability and the prevalence of SIBO correlated with the severity of steatosis but not with presence of NASH. CONCLUSIONS: Our results provide the first evidence that NAFLD in humans is associated with increased gut permeability and that this abnormality is related to the increased prevalence of SIBO in these patients. The increased permeability appears to be caused by disruption of intercellular tight junctions in the intestine, and it may play an important role in the pathogenesis of hepatic fat deposition.

Extragastric manifestations of Helicobacter pylori infection.

The possible role of Helicobacter pylori as a trigger for some extragastric diseases has been largely investigated in the last year. There are, in fact, several studies concerning cardiovascular diseases, neurological disorders, diabetes mellitus, ear and eyes diseases, immunological and hematological disorders, liver and bile tract diseases, gynecological and respiratory tract pathologies. Among them, idiopathic sideropenic anemia and idiopathic thrombocytopenic purpura still remain the extragastric diseases showing the most convincing results. Concerning ischemic heart disease, there are new interesting data playing in favor of the association, even though there are still some open issues to be clarified. For the other diseases, more studies are needed to clarify the reality of the proposed association.

When was celiac disease born?: the Italian case from the archeologic site of Cosa.

A case of a young woman died in Italy during the first century AD is presented. She had short height (140 cm), clinical history of anemia, and a decreased bone mass with evidence of osteoporosis and bone fragility. The archeologic artifacts from the tomb and with the quality of burial architecture suggest that the tomb was built for a rich person in an area with extensive culture of wheat. The wellness of the area is supported by the lack of other bodies found with signs of malnutrition. Clinical presentation and the possible continuous exposure to wheat seem to suggest a case of celiac disease. This case could be the first case of this condition since that one described by Areteus of Cappadocia in 250 BC and could be helpful to clarify the phylogenetic tree of celiac disease.

[Recent knowledge on the pathogenesis of nonalcoholic fatty liver disease. Role of genetic factors]. / Recenti acquisizioni sulla patogenesi della steatosi epatica non alcolica: il ruolo dei fattori genetici.

The Non-Alcoholic Fatty Liver Disease (NAFLD) is the most frequent cause of chronic liver disease in West, potentially associated with an elevated morbidity and mortality. The search is busy in to identify genetic factors of progression in people with same environmental risk factors. Objective of this review is to analyze the data from association studies on the role of the genetic factors in NAFLD. The available studies are not conclusive in to identify candidate genes, because conducted on small populations and with not well-done designs. Identification of genetic risk profiles for NAFLD progression could help to individualize the patients treatment and follow-up.

[Helicobacter pylori infection: from gastric to systemic disease]. / Manifestazioni extragastriche dell'infezione da Helicobacter pylori.

H. pylori infection, through a chronic stimulation of the immune system and the occurrence of molecular mimicry mechanisms, is responsible for the majority of the gastroduodenal diseases and also for some extragastric disorders, including sideropenic anemia and idiopathic thrombocytopenic purpura; other diseases are under investigation.

[Focal myocarditis mimicking ST-elevation myocardial infarction in a patient with Helicobacter pylori infection: role of magnetic resonance with late gadolinium enhancement]. / Miocardite simulante un infarto miocardico acuto con sopraslivellamento del tratto ST in paziente con infezione da Helicobacter pylori: ruolo della risonanza magnetica con late gadolinium enhancement.

Myocarditis is an emerging disease. We have investigated a case of focal myocarditis with ventricular thrombus in a patient with Helicobacter pylori infection who came to our attention for the persistence of chest pain one week after previous discharge. The patient was before and otherwise misunderstood as myocardial infarction and recognized in our Centre as myocarditis by magnetic resonance. Diagnostic iter was focused on understanding the pathogenesis of the previous reported cardiac event as well as a link with the persistence of chest pain finally found related to Helicobacter pylori infection. We briefly discuss about role and some caveats of magnetic resonance with late gadolinium enhancement as new diagnostic approach of myocarditis, compared to myocardial biopsy.